madman
Super Moderator
* This is the largest study to date characterizing testosterone to estradiol ratios in men presenting for fertility evaluation. We validated the 10/1 ratio that was previously established as the 20th percentile for fertile men.
OBJECTIVE
To validate the established normal testosterone to estradiol ratio and characterize the distribution of testosterone to estradiol ratios in a large cohort of fertile and subfertile men.
MATERIALS AND METHODS
Retrospective review of adult men (≥18 years of age) presenting for fertility evaluation between 2002 and 2021 who underwent evaluation by a reproductive urologist, had 2 separate semen analyses and had hormonal testing within 6 months of their index semen analysis. Men were dichotomized into fertile and subfertile groups based on total motile sperm count on 2 semen analyses. The subfertile cohort included men with a total motile sperm count < 20 million on both semen analyses. The main outcome measures were serum testosterone, serum estradiol, and serum testosterone to estradiol ratio.
RESULTS
Among 816 men, 651 (79.8%) were classified as fertile and 165 (20.2%) as subfertile. Median testosterone (ng/dL) to estradiol (pg/mL) ratios were similar between the groups (14.48 vs 15.00, P = .5). The 20th percentile testosterone to estradiol ratio for the fertile group was 9.77.
CONCLUSION
This is the largest study to date characterizing testosterone to estradiol ratios in men presenting for fertility evaluation. We validated the 10/1 ratio that was previously established as the 20th percentile for fertile men. We found no difference in testosterone to estradiol ratios between fertile and subfertile men defined by total motile sperm count, highlighting the need for further investigation to better define the cohort of men with infertility who could benefit from aromatase inhibitor therapy.
Infertility affects 1 out of 6 couples, and although the role of male factor infertility is difficult to quantify, prior studies have shown that male factor infertility is implicated in up to 40% and solely responsible for 10%-20% of infertile couples.1,2 The evaluation and management of male factor infertility has progressed significantly in recent years, but the optimal evaluation and management strategy remains controversial due to many confounders and the lack of clinical trials.3
The American Urologic Association (AUA) and American Society of Reproductive Medicine (ASRM) guidelines recommend an endocrine evaluation in the assessment of infertility in men when clinical evidence suggests an underlying endocrinopathy. However, some experts advocate for an endocrine evaluation in all male infertility patients.4 When an endocrinopathy is identified, it can be targeted with medications including aromatase inhibitors (AIs), human chorionic gonadotropin (hCG), and selective estrogen receptor modulators(SERMs).5
The delicate equilibrium of testosterone (T) and estradiol (E) levels both systemically and in the testicular micro-environment are thought to have a significant effect on spermatogenesis, although the exact mechanisms remain unknown.6-8 A landmark study by Pavlovich et al in 2001 supported the conclusion that some men with infertility have a treatable endocrinopathy represented by a low T/E ratio.9 This study defined a normal T/E ratio as 10/1 based on the 20th percentile distribution of a reference group of 40 fertile men.9 The authors also studied a cohort of men with severe male factor infertility and characterized semen parameter improvement with AI treatment in men with a T/E ratio less than 10/1.9 This established normal ratio of 10/1 tha thas been carried forward in subsequent literature and trials. While the first of its kind, the study was limited by the small number of participants and the broad inclusion criteria for the infertile group including soft small testes, increased follicle-stimulating hormone (FSH), or abnormal semen analysis (SA).
To our knowledge, there have not been further studies that have reassessed the established normal T/E ratio.There have been calls to avoid utilizing the 10/1 ratio asa cutoff in the absence of further research efforts validating the definition of a low T/E ratio.10 Given that the AUA and ASRM guidelines discuss the option of utilizing AI treatment in infertile men, we believe it is critical to reassess the previously described T/E threshold with a larger cohort.5 We sought to characterize the T/E ratio distribution in a larger, contemporary cohort and to compare T/E ratios among fertile and subfertile men presenting for fertility evaluation.
Discussion
Despite similarities in the overall distribution of T/E ratios between fertile and subfertile men, prior studies have shown that specific groups of subfertile men may benefit from treatment with an AI. In men with impaired semen parameters, AI therapy increases serum testosterone and decreases serum estradiol, thus raising the T/E ratio, while also having a positive effect on semen parameters.9,10,13-16 In general, testosterone deficiency is often implicated in men with oligospermia, and there is an established correlation between semen parameters and low serum testosterone levels.5,17 Likewise, the role of estradiol in the feedback pathways of the hypothalamic-pituitary-gonadal axis has been well established and may impact semen parameters. As such, it remains unclear whether the benefit of AI therapy is specifically driven by changes in serum testosterone, serum estradiol, T/E ratio, or some combination thereof.
Given the potential benefits of AI therapy, criteria are needed to determine the optimal candidates for treatment. Certainly, men with high estradiol levels and symptomatic hyperestrogenism warrant treatment. However, among asymptomatic men, the parameters for treatment remain unknown. While the current study validates the ratio of 10/1 as the 20th percentile of both fertile and subfertile populations, it is unclear whether this is a reasonable clinical cutoff for treatment initiation. The lower bound of the normal range for a variety of other laboratory parameters is typically established at a lower percentile of the normal distribution. For example,WHO reference ranges utilize the 5th percentile of fertile men as the lower bound for all bulk semen parameters. We found that the 5th percentile for T/E ratio was approximately 6/1, and it is possible that this may be a more reasonable clinical cutoff for treatment initiation. In our study, 42 patients would be eligible for AI treatmentinitiation if this 6/1 ratio (5th percentile) was used as a cutoff, compared to 171 patients if the 10/1 ratio (20th percentile) was used. Naelitz et al described other predictors (T:LH ratio > 100) of spermatogenic response to AI treatment, and further, larger studies are needed to establish reasonable criteria for AI treatment in the asymptomatic patient.18
CONCLUSION
In this retrospective study, we characterized the distribution of T/E ratio in a large cohort of men presenting for fertility evaluation. We validated the 10/1 ratio that was previously established as the 20th percentile for fertile men, and we found no difference in T/E ratio between fertile and subfertile men defined by TMSC. Additional studies are needed to better define the cohort of men with infertility who could benefit from the use of AI therapy, and the distribution of T/E ratios characterized herein can inform future clinical trial design and possibly clinical practice.
OBJECTIVE
To validate the established normal testosterone to estradiol ratio and characterize the distribution of testosterone to estradiol ratios in a large cohort of fertile and subfertile men.
MATERIALS AND METHODS
Retrospective review of adult men (≥18 years of age) presenting for fertility evaluation between 2002 and 2021 who underwent evaluation by a reproductive urologist, had 2 separate semen analyses and had hormonal testing within 6 months of their index semen analysis. Men were dichotomized into fertile and subfertile groups based on total motile sperm count on 2 semen analyses. The subfertile cohort included men with a total motile sperm count < 20 million on both semen analyses. The main outcome measures were serum testosterone, serum estradiol, and serum testosterone to estradiol ratio.
RESULTS
Among 816 men, 651 (79.8%) were classified as fertile and 165 (20.2%) as subfertile. Median testosterone (ng/dL) to estradiol (pg/mL) ratios were similar between the groups (14.48 vs 15.00, P = .5). The 20th percentile testosterone to estradiol ratio for the fertile group was 9.77.
CONCLUSION
This is the largest study to date characterizing testosterone to estradiol ratios in men presenting for fertility evaluation. We validated the 10/1 ratio that was previously established as the 20th percentile for fertile men. We found no difference in testosterone to estradiol ratios between fertile and subfertile men defined by total motile sperm count, highlighting the need for further investigation to better define the cohort of men with infertility who could benefit from aromatase inhibitor therapy.
Infertility affects 1 out of 6 couples, and although the role of male factor infertility is difficult to quantify, prior studies have shown that male factor infertility is implicated in up to 40% and solely responsible for 10%-20% of infertile couples.1,2 The evaluation and management of male factor infertility has progressed significantly in recent years, but the optimal evaluation and management strategy remains controversial due to many confounders and the lack of clinical trials.3
The American Urologic Association (AUA) and American Society of Reproductive Medicine (ASRM) guidelines recommend an endocrine evaluation in the assessment of infertility in men when clinical evidence suggests an underlying endocrinopathy. However, some experts advocate for an endocrine evaluation in all male infertility patients.4 When an endocrinopathy is identified, it can be targeted with medications including aromatase inhibitors (AIs), human chorionic gonadotropin (hCG), and selective estrogen receptor modulators(SERMs).5
The delicate equilibrium of testosterone (T) and estradiol (E) levels both systemically and in the testicular micro-environment are thought to have a significant effect on spermatogenesis, although the exact mechanisms remain unknown.6-8 A landmark study by Pavlovich et al in 2001 supported the conclusion that some men with infertility have a treatable endocrinopathy represented by a low T/E ratio.9 This study defined a normal T/E ratio as 10/1 based on the 20th percentile distribution of a reference group of 40 fertile men.9 The authors also studied a cohort of men with severe male factor infertility and characterized semen parameter improvement with AI treatment in men with a T/E ratio less than 10/1.9 This established normal ratio of 10/1 tha thas been carried forward in subsequent literature and trials. While the first of its kind, the study was limited by the small number of participants and the broad inclusion criteria for the infertile group including soft small testes, increased follicle-stimulating hormone (FSH), or abnormal semen analysis (SA).
To our knowledge, there have not been further studies that have reassessed the established normal T/E ratio.There have been calls to avoid utilizing the 10/1 ratio asa cutoff in the absence of further research efforts validating the definition of a low T/E ratio.10 Given that the AUA and ASRM guidelines discuss the option of utilizing AI treatment in infertile men, we believe it is critical to reassess the previously described T/E threshold with a larger cohort.5 We sought to characterize the T/E ratio distribution in a larger, contemporary cohort and to compare T/E ratios among fertile and subfertile men presenting for fertility evaluation.
Discussion
Despite similarities in the overall distribution of T/E ratios between fertile and subfertile men, prior studies have shown that specific groups of subfertile men may benefit from treatment with an AI. In men with impaired semen parameters, AI therapy increases serum testosterone and decreases serum estradiol, thus raising the T/E ratio, while also having a positive effect on semen parameters.9,10,13-16 In general, testosterone deficiency is often implicated in men with oligospermia, and there is an established correlation between semen parameters and low serum testosterone levels.5,17 Likewise, the role of estradiol in the feedback pathways of the hypothalamic-pituitary-gonadal axis has been well established and may impact semen parameters. As such, it remains unclear whether the benefit of AI therapy is specifically driven by changes in serum testosterone, serum estradiol, T/E ratio, or some combination thereof.
Given the potential benefits of AI therapy, criteria are needed to determine the optimal candidates for treatment. Certainly, men with high estradiol levels and symptomatic hyperestrogenism warrant treatment. However, among asymptomatic men, the parameters for treatment remain unknown. While the current study validates the ratio of 10/1 as the 20th percentile of both fertile and subfertile populations, it is unclear whether this is a reasonable clinical cutoff for treatment initiation. The lower bound of the normal range for a variety of other laboratory parameters is typically established at a lower percentile of the normal distribution. For example,WHO reference ranges utilize the 5th percentile of fertile men as the lower bound for all bulk semen parameters. We found that the 5th percentile for T/E ratio was approximately 6/1, and it is possible that this may be a more reasonable clinical cutoff for treatment initiation. In our study, 42 patients would be eligible for AI treatmentinitiation if this 6/1 ratio (5th percentile) was used as a cutoff, compared to 171 patients if the 10/1 ratio (20th percentile) was used. Naelitz et al described other predictors (T:LH ratio > 100) of spermatogenic response to AI treatment, and further, larger studies are needed to establish reasonable criteria for AI treatment in the asymptomatic patient.18
CONCLUSION
In this retrospective study, we characterized the distribution of T/E ratio in a large cohort of men presenting for fertility evaluation. We validated the 10/1 ratio that was previously established as the 20th percentile for fertile men, and we found no difference in T/E ratio between fertile and subfertile men defined by TMSC. Additional studies are needed to better define the cohort of men with infertility who could benefit from the use of AI therapy, and the distribution of T/E ratios characterized herein can inform future clinical trial design and possibly clinical practice.
